This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Goal 1: To test the hypothesis that subsets of Clara cells in different locations give rise to adenocarcinomas of different phenotypes Clara cells in human airways represent a potential stem cell-of-origin for adenocarcinoma. We have generated a mouse model for activation of K-RasG12D in secretory (Clara) cells expressing Scgb1a1(CC10) in different locations: the distal lung and BADJ, the larger airway, and the trachea. We found that these mice develop surfactant protein C (SPC)-positive tumors around the bronchoalveolar duct junction but also largely SPC-negative tumors in the proximal airways. We will isolate tumors of each type and compare their transcriptome profiles to each other and to isolated wild-type Clara cells. This will provide insight into potential differences in tumor biology related to cell of origin. Goal 2: To test the hypothesis that coexpression of potentially oncogenic transcription factors Sox2 and Nkx2.1 with the Kras mutant in Clara cells and other bronchial epithelial cells leads to tumors of different histologies and behaviors. Recent data from human tumors has implicated NKX2.1 (TTF1) and SOX2 as potential oncogenes in adenocarcinoma and squamous cell carcinoma respectively. We have generated mouse lines carrying inducible Nkx2.1 or Sox2 alleles and have begun crossing them to the CC10CreER-Kras mutant mice. In addition, crosses to K5CreER, SPCCreER, and FoxJ1CreER are underway. The resulting tumors, if any, will be investigated for location, histology, growth rate, and transcriptome profile. Goal 3: To test the hypothesis that Ras-driven transgenic mouse lung adenocarcinoma will be susceptible to certain chemotherapeutic agents and that susceptibility will change after treatment. The transcriptome profile of the Ras mutant-induced tumors will be compared to several known chemotherapeutic sensitivity profiles generated using tumor cell lines at Duke. The mice will be administered agents to which they are predicted sensitive or resistant. The survival of the mice as well as the genomic profiles of residual tumors will be investigated.